Summary of work: As part of our program of research on early markers of Alzheimers disease, we are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early predictors of cognitive change and impairment, including Alzheimer's disease (AD). We are continuing longitudinal testing of older participants and evaluating new participants, including MRI and concurrent neuropsychological assessments of participants less than 55 years old. For a subsample of individuals aged 55 and older, we also perform a single PET measurement of cerebral blood flow, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid distribution. Our progress over the last year includes continued acquisition of new neuroimaging assessments as well as continued analysis of existing data and methods development. The MRI research protocol has been expanded to all BLSA participants eligible for MRI scanning and includes a resting state functional MR (rsfMR) and task activated fMR, alternating between a decision making task and an associative memory task. Approximately half of the neuroimaging study participants are enrolled in the BLSA autopsy program, and we continue to use the 3-dimensional imaging findings to guide neuropathological investigations. In addition, we are using neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in cognitive and brain aging, genetic, metabolic, and inflammatory risk factors, and the effects of sex steroid and other hormones. An understanding of these brain-behavior associations and early detection of accelerated brain changes during the preclinical or asymptomatic stage of disease will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of disease is available. These studies also inform the neurobiology and temporal progression of presymptomatic changes in Alzheimer's disease and may point to new targets for treatments. Over the last year, we have published a number of papers describing a variety of results from the BLSA neuroimaging study. Expanding on our prior work identifiying changes in brain function occurring years before cognitive impairment, we investigated cortical thinning over time in BLSA participants who remained cognitively normal versus those who subsequently developed cognitive impairment (Pacheco et al., 2015). We demonstrated wide-spread cortical thinning in individuals who remained normal, but regionally selective greater thinning in participants who subsequently developed cognitive impairment. Even though all participants were cognitively normal at the time of all MRI scans, the subgroup who developed subsequent cognitive impairment showed greater thinning in the temporal lobe, most pronounced in the medial temporal lobe, compared to those who remained normal. These findings show that specific brain changes accelerate in the earliest asymptomatic stages of disease. In another study, we found that hypertension is one factor that may modulate rates of cortical thinning (Gonzalez et al, 2015). Comparing hypertensives to normotensives, we found that hypertensive individuals show an increased rate of thinning compared with normotensive individuals in several regions, including the frontomarginal gyrus in the left hemisphere, and the superior temporal, fusiform, and lateral orbitofrontal cortex in the right hemisphere. In collaboration with Dr. Marilyn Albert and her team at Johns Hopkins University, we showed changes over time in amyloid-betta(A&#946;)in two longitudinal cohorts with different biomarkers of amyloid-beta and investigated how level and change in A&#946; is modified by Apolipoprotein E (APOE)&#949;4 genotype (Resnick et al, 2015). We used 11-C-Pib PET imaging of A&#946; in 113 BLSA participants and cerebrospinal fluid (CSF) A&#946; in 207 BIOCARD study participants to demonstrate longitudinal increases in brain A&#946; and decreases in CSF A&#946;. Moreover, APOE &#949;4 genotype was significantly associated with higher PET-PiB retention and lower CSF A&#946;1-42, independent of age and sex, but APOE genotype did not significantly affect A&#946; change over time. These findings suggest that APOE &#949;4 carriers may be further along in the disease process, consistent with earlier brain A&#946; deposition, and providing a biological basis for APOE genotype effects on onset age of Alzheimer's disease. As part of this research program, we have continued to perform a number of methodological studies to optimize the application of our neuroimaging approaches. In an important study, we investigated voxel-wise correlations between cerebral blood flow and PET-PiB retention (Sojkova et al., 2015). We found higher associations between blood flow and PiB in the group with the lowest global cortical PiB retention compared to the high global PIB retention group. These findings show that regional patterns of PiB retention at neglible amyloid levels reflect blood flow and tracer delivery than regional amyloid levels. This finding has critical implications for voxel-wise correlation of PiB or other amyloid PET scans with other outcomes, e.g. cognitive performance. In addition, work under this project has led to the development of an approach using a deformable template to define regions of interest on PET scans where MRI scans are not available (Bilgel et al., 2015). In another methodological study, we investigated the test-retest stability and scan-to-scan reliability of regional diffusion tensor imaging (DTI) scans acquired on scanners from different vendors and different field strengths (Venkatraman et al., 2015). We highlighted specific indices and regions that could be consistently measured and showed how measurement stability could be enhanced by statistical incorporation of a scanner correction factor.